title: Serum concentrations of rufinamide in children and adults with epilepsy: the influence of dose, age, and comedication.
abstract: Rufinamide (RUF) is an orphan drug for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in persons aged 4 years and older. Several studies have investigated the pharmaconkinetics of RUF, but information about interactions is still limited and the results are in part inconsistent. The aim of our study was to analyze the effect of age, gender, daily RUF dose per body weight (mg/kg), valproic acid (VPA), and enzyme-inducing antiepileptic drugs (EIAEDs) on RUF concentration-to-dose ratio (RUF serum concentration/RUF dose per body weight), RUF clearance (RUF dose/RUF serum concentration), and RUF trough concentrations. Different statistical methods were used to evaluate 292 blood samples from 119 patients who fulfilled the inclusion criteria. In summary, the results using generalized estimating equation regression models confirm a moderate but statistically significant nonlinear RUF concentration-dose relationship. At steady state, the trough concentrations of RUF increase in a less than dose proportional manner. Children (younger than 12 years) had significantly lower RUF concentrations (19.0%, P < 0.001) than adults (18 years or older) on comparable RUF doses per body weight. VPA was the most frequent comedication (51%) in our patient group. Mean RUF concentrations were 86.6% higher when VPA concentrations were greater than 90 μg/mL (P < 0.001) and 45.4% higher when VPA concentrations were between 50 and 90 μg/mL (P < 0.001) but not significantly different at VPA concentrations less than 50 μg/mL (4.4%, P > 0.1) compared with combinations without VPA. In combination with EIAEDs, mean RUF concentrations were 21.8% lower (P = 0.002) compared with combinations without EIAEDs. However, the group of AEDs classified as EIAEDs was heterogeneous and the number of patients, especially of children with EIAEDs, was relatively small. Our data indicate that oxcarbazepine and, especially, methsuximide decrease RUF concentrations as well. Therapeutic drug monitoring might be helpful because RUF concentrations differ markedly in patients on comparable RUF doses.
authors.affiliation: Pharmacological Laboratory, Society for Epilepsy Research, Bielefeld, Germany. Theodor.May@evkb.de
authors.forename: Theodor W
authors.initials: TW
authors.lastname: May
authors.forename: Rainer
authors.initials: R
authors.lastname: Boor
authors.forename: Bernhard
authors.initials: B
authors.lastname: Rambeck
authors.forename: Uwe
authors.initials: U
authors.lastname: Jürgens
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Korn-Merker
authors.forename: Christian
authors.initials: C
authors.lastname: Brandt
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000927:Anticonvulsants / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001835:Body Weight; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000097:blood / Q000188:drug therapy*; D065768:Lennox Gastaut Syndrome; D008297:Male; D008875:Middle Aged; D012640:Seizures / Q000188:drug therapy; D013036:Spasms, Infantile / Q000097:blood / Q000188:drug therapy*; D014230:Triazoles / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D014635:Valproic Acid / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D014230:Triazoles; D014635:Valproic Acid; C079703:rufinamide